1. Field of the Invention
This invention relates to a method for treating disease using a 20(S)-camptothecin and an anthracycline, and more specifically a method for treating disease using a 20(S)-camptothecin and an anthracycline in a sequential therapy.
2. Description of Related Art
A. 20(S)-Camptothecins
20(S)-camptothecin, a plant alkaloid, was found to have anticancer activity in the late 1950""s. Wall, M. et al., Plant antitumor agents. I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata, J. Am. Chem. Soc. 88: 3888-3890, (1966); Monroe E. Wall et al., Camptothecin: Discovery to Clinic, 803 Annals of the New York Academy of Sciences 1 (1996). These documents, and all documents articles, patents, etc.) cited to herein, are incorporated by reference into the specification as if reproduced fully below. The chemical formula of camptothecin was determined to be C20H16 N2 O4.
20(S)-camptothecin itself is insoluble in water. However, during the sixties and seventies the sodium salt of 20(S)-camptothecin was derived from 20(S)-camptothecin through opening of the lactone ring using a mild base. Clinical trials were then conducted using this hydrosoluble, sodium salt derivative of 20(S)-camptothecin 20(S)-camptothecin Na+), which was administered intravenously. The studies were later abandoned because of the high toxicity and low potency of 20(S)-camptothecin Na+. Gottlieb, J. A., et al., Preliminary pharmacological and clinical evaluation of camptothecin sodium salt (NSC 100880), Cancer Chemother. Rep. 54:461-470 (1979); Muggia, F. M., et al., Phase I clinical trials of weekly and daily treatment with camptothecin (NSC 100880): Correlation with clinical studies, Cancer Chemother. Rep. 56:515-521 (1972); Gottlieb, J. A. et al., Treatment of malignant melanoma with camptothecin (NSC 100880), Cancer Chemother. Rep. 56:103-105 (1972); and Moertel, C. G., et al., Phase II study of camptothecin (NSC 100880) in the treatment of advanced gastrointestinal cancer, Cancer Chemother Rep. 56:95-101 (1972).
Despite its potential, interest in 20(S)-camptothecin as a therapeutic remained at a low ebb until the mid-1980""s. By that time, drug therapies were being evaluated for treating human cancer using human cancer xenograft lines. During these evaluations, human tumors are serially heterotransplanted into immunodeficient, so-called Anude@ mice, and the mice then tested for their responsiveness to a specific drug (Giovanella, B. C., et al., Cancer 52(7): 1146 (1983)). The data obtained in these studies strongly support the validity of heterotransplanted human tumors into immunodeficient mammals, such as nude mice, as a predictive model for testing the effectiveness of anticancer agents.
20(S)-camptothecin, and later some of its substituted forms, elicited differential responses in the cell cycle of nontumorigenic and tumorigenic human cells in vitro. Although it is not yet understood why 20(S)-camptothecin and some of its substituted forms are cytostatic for nontumorigenic cells and cytotoxic for tumorigenic cells, the selective toxicity of the compounds against tumorigenic cells in vitro and in vivo was an especially interesting feature of these drugs.
Investigators began to experiment with various substituted forms of 20(S)-camptothecin. Good activity was found when various substitutions were made to the 20(S)-camptothecin scaffold. For example, (9-Amino-20(S)-Camptothecin (9AC) and 10,11-Methylendioxy-20(S)-Camptothecin (10,11 MD) are capable of having high anticancer activity against human colon cancer xenografts. Giovanella, B. C., et al., Highly effective topoisomerase-1 targeted chemotherapy of human colon cancer in xenografts, Science 246:1046-1048 (1989).
Additionally, 9-nitrocamptothecin (9NC) has shown high activity against human tumor xenograft models. 9NC has a nine position hydrogen substituted with a nitro moiety. 9NC has inhibited the growth of human tumor xenografts in immunodeficient nude mice and has induced regression of human tumors established as xenografts in nude mice with little or no appearance of any measurable toxicity. D. Chatterjee et al., Induction of Apoptosis in Malignant and Camptothecin-resistant Human Cells, 803 Annals of the New York Academy of Sciences 143 (1996).
U.S. Pat. No. 5,552,154 to Giovanella et al. disclosed methods of treating specific forms of cancer with water-insoluble 20(S)-camptothecin and derivatives thereof, having the closed-lactone ring intact. In particular, transdermal, oral and intramuscular methods of administration using solutions of water-insoluble 20(S)-camptothecin were disclosed.
Other substituted 20(S)-camptothecin compounds that have shown promise include 7-ethyl-10-hydroxy 20(S)-camptothecin, and other 7, 9, 10, 11-substituted compounds.
B. Anthracyclines
Anthracyclines are commonly known to be highly active antineoplastic agents. Anthracyclines include rhodomycin derivatives, including doxorubicin, duanorubicin, idarubicin, epirubicin, and mitoxantrone, as well as agents such as aclacinomycin A and related compounds.
Anthracyclines are known cytostatic agents, e.g., they inhibit or suppress cell growth and multiplication. Antracyclines act by an incompletely understood mechanism, which includes some antihelicase activity, and have been observed to exert a differentiation-inducing effect.
Anthracyclines, which comprise a four membered anthracycline nucleus attached to a sugar molecule, are clinically important anti-neoplastic agents. Doxorubicin is widely used in treating several solid tumors while daunorubicin and idarubicin are used exclusively for the treating leukemias. Daunorubicin and doxorubicin are identical except for the presence of a hydrogen or hydroxyl at position 14 of the anthracycline ring. Idarubicin, 4-demethoxy-daunorubicin, is a new anthracycline in which the structural modification at position 4 of the chromophore ring increases lipophilicity and half-life.
Anthracyclines bind double stranded DNA by intercalation as has been demonstrated experimentally. Their cytotoxicity largely results from this binding. Human chromosome preparations treated with anthracyclines exhibit the bound drug as defined, orange-red fluorescent bands. If structure of the anthracyclines is modified to reduce intercalative binding of DNA, a decrease or loss of antitumor activity is usually observed. Thus, DNA binding appears critical for anti-neoplastic activity of these drugs.
The specific mechanism of cytotoxicity is not clearly understood. Because inhibition only of DNA and RNA synthesis occurs at high drug concentration only, it is not thought critical to cytotoxicity. Anthracyclines exert a number of cellular physiologic effects, any one or a combination of which may mechanistically effect their cytotoxicity.
By intercalating DNA, anthracyclines can affect many functions of the DNA including DNA and RNA synthesis. Breakage of the DNA strand can also occur. This is believed to mediated either by inhibition of the enzyme DNA Topoisomerase II (hTopII) or by the formation of free radicals. Inhibition of the enzyme hTopII, for example, can lead to a series of reactions leading to double strand breaks in the DNA. Thus the mechanism of action of anthracyclines is complex and at best poorly understood.
As camptothecin inhibits human topoisomerase I (hTopI) which possesses multiple enzymatic activities. It influences the topology of DNA as does hTopII, which is evidenced to be inhibited by the anthracyclines. But hTopI is also capable of phosphorylating proteins essential for mRNA splicing, evidencing hTopI involvement in the RNA splicing process. Inhibitors of hTopI such as camptothecins are therefore important anti-neoplastic pharmacotherapeutic agents.
Because hTopI, a 765-amino-acid nuclear enzyme (Stewart et al. (1996) J. Biol. Chem. 271:7593-601) involved in topological changes of DNA structure (Pommier et al. 1998) Biochim. Biophys. Acta 1400:83-106), plays key roles in DNA replication, transcription, and recombination, collectively DNA metabolism. During the hTopI catalytic process, a transient covalent linkage, termed a xe2x80x98cleavable complexxe2x80x99, forms between hTopI and DNA strand nicks. Camptothecins specifically target hTopI, binding noncovalently to cleavable complexes, to stabilize them and inhibit religation (Fan et al. 1998) J. Med. Chem. 41:2216-26), promoting formation of single-and double-strand DNA breaks, resulting in premature termination of replication and inhibition of transcription (Bendixen et al. (1990) Biochemistry 29:5613-19). Cells can repair DNA breaks, permitting cell survival with exposure to low doses of camptothecins, but higher doses lead to cell death (Darzynkiewicz et al. 1996) Ann. N. Y. Acad. Sci. 803:90-100). Because many neoplastic cells exhibit high levels and/or activities of hTopI Giovanella et al. (1989) Science 246:1046-48; Husain et al. (1994) Cancer Res. 54: 539-46), hTopI has become a cellular target for anticancer chemotherapy O""Leary et al. (1998) Eur. J. Cancer. 34:1500-08; Takimoto et al. (1998) Biochim. Biophys. Acta 1400:107-119). Camptothecin derivatives such as topotecan and irinotecan (CPT-11) are currently used in the treatment of various cancers O""Leary et al. 1998) supra; Takimoto et al. (1998) supra; Beran et al, (1998) Semin Oncol 35:26-31). In patients who received high doses of hTopI inhibitors, only limited side effects, such as manageable neutropenia, have been reported O""Leary et al. (1998) supra; Takimoto et al. (1998) supra).
Although hTopI and hTopII are structurally diverse enzymes that generate transient single or double strand breaks in the DNA phosphodiester backbone to allow the passage of one or two DNA strands during replication by apparently different mechanisms, certain intercalating agents have been reported to inhibit both. This observation further complicates the current understanding of the mechanisms of action and inhibition of these two enzymes. Specifically, DNA-intercalating tricyclic carboxamides have the dual activity of both hTopI and hTopII inhibition Malonne et al. (1997) Anti-Cancer Drugs 8:811-22). The crystal structure of several such compounds with the DNA sequence CG(5BrU)ACG reveals a quadruplex-like intercalation cavity.
Thorpe et al. (2000) Biochemistry 39:15055-61 have previously shown that 9-aminoacridinecarboxamides hTopII inhibitors) can intercalate into duplex DNA, with the carboxamide side chain oriented by H-bonding to the cationic ring nitrogen of the acridine to lie in the major groove; thus oriented they specifically bind to adjacent guanines (Todd et al. (1999) J. Med Chem. 42:536-40). These observations, and consistent data obtained using purified topoisomerases in vitro to study drug-induced cleavable complex formation, suggest that the tricyclic carboxamides have different binding sites, altered sequence specificity or a different mechanism of action from other topoisomerase poisons. Thus the mechanisms of the hTopI and hTopII inhibitory activity of camptothecins and anthracyclines respectively are incompletely understood with respect to DNA physiology. Indeed the additionally evidenced effects of hTopI that do not involve DNA metabolism, evidence of the roles hTopII and hTopII play in cellular physiology in general, are poorly understood.
In U.S. Pat. No. 5,786,344 to Ratain et al., numerous genera of agents, including anthracyclines, are listed for possible combination with camptothecins. Bertrand et al. (1992) Eur. J. Cancer, 28A(4-5):743-48 observed an antagonism from simultaneous administration of the hTopI inhibitor and hTopII inhibitor. Various antineoplastic sequential therapies in which hTopI inhibitors, including camptothecins are found effective when administered prior to agents that are not hTopI inhibitors. See for example, Mori et al. (1993) Int. J. Gynecol. Cancer: 3(1):36-43.
A method is provided for treating a patient having a disease associated with undesirable or uncontrolled cell proliferation, the method comprising: administering to the patient an anthracycline for a period of time during which a 20(S)-camptothecin is not being administered to the patient; and administering a 20(S)-camptothecin to the patient.
According to this method, the anthracycline is optionally administered at least 10, 20, 30, 40, 50, or more days before the 20(S)-camptothecin is administered. Also according to this method, the anthracycline is optionally administered between 10 and 120 days, 20 and 120 days, 30 and 120 days, 40 and 120 days, or 50 and 120 days before the 20(S)-camptothecin is administered.
Also according to this method, the anthracycline is optionally administered at least 10, 20, 30, 40, 50, or more days after the 20(S)-camptothecin is administered. Also according to this method, the anthracycline is optionally administered between 10 and 120 days, 20 and 120 days, 30 and 120 days, 40 and 120 days, or 50 and 120 days after the 20(S)-camptothecin is administered.
Also according to this method, the anthracycline is optionally administered between 10 and 120 days, 20 and 120 days, 30 and 120 days, 40 and 120 days, or 50 and 120 before and/or after the 20(S)-camptothecin is administered and is also administered within that period of time when the 20(S)-camptothecin is administered.
A method is also provided for treating a patient having a disease associated with undesirable or uncontrolled cell proliferation, the method comprising: administering to the patient an anthracycline for a period of time during which a 20(S)-camptothecin is not present in a pharmacologically active form in the patient""s body; and administering a 20(S)-camptothecin to the patient.
According to this method, the anthracycline is optionally administered at least 10, 20 30, 40, 50, or more days before the 20(S)-camptothecin is present in a pharmacologically active form in the patient""s body. Also according to this method, the anthracycline is optionally administered between 10 and 120 days, 20 and 120 days, 30 and 120 days, 40 and 120 days, or 50 and 120 before the 20(S)-camptothecin is present in a pharmacologically active form in the patient""s body.
Also according to this method, the anthracycline is optionally administered at least 10, 20, 30, 40, 50, or more days after the 20(S)-camptothecin is present in a pharmacologically active form in the patient""s body. Also according to this method, the anthracycline is optionally administered between 10 and 120 days, 20 and 120 days, 30 and 120 days, 40 and 120 days, or 50 and 120 after the 20(S)-camptothecin is present in a pharmacologically active form in the patient""s body.
Also according to this method, the anthracycline is optionally administered between 10 and 120 days, 20 and 120 days, 30 and 120 days, 40 and 120 days, or 50 and 120 before or after the 20(S)-camptothecin is present in a pharmacologically active form in the patient""s body and is also administered when the 20(S)-camptothecin is present in a pharmacologically active form in the patient""s body.
In regard to the methods of the present invention, in one variation, the anthracycline is selected from the group consisting of: doxorubicin, duanorubicin, idarubicin, epirubicin, and mitoxantrone and aclacinomycin A. In one particular variation, the anthracycline is doxorubicin.
In regard to the methods of the present invention, in one variation, the 20(S)-camptothecin is 9-nitro-20(S)-camptothecin.
In regard to the methods of the present invention, in one variation, the disease associated with undesirable or uncontrolled cell proliferation is cancer. Examples of cancers include, but are not limited to acute myelogenous leukemia, cholangiocarcinoma, chronic myelogenous leukemia, lymphoma, melanoma, multiple myeloma, osteosarcoma, gastric sarcoma, glioma, bladder, breast, cervical, colorectal, lung, ovarian, pancreatic, prostrate, and stomach cancer.